(a) Field of the Invention
This invention is concerned with analgesic compounds, processes for making them and the compounds thus prepared, various intermediates useful in their synthesis, and pharmaceutical compositions incorporating these analgesic compounds. More especially, the invention relates to N-acetyl-para-aminophenyl N'-acetylaminothioalkanoates which are useful as analgesic agents having analgesic activity like that of N-acetyl-para-aminophenol but being largely free from the hepatotoxic effects normally encountered when N-acetyl-para-aminophenol is taken in overdose.
(b) Description of the Prior Art
The compound N-acetyl-para-aminophenol, also known as acetaminophen, paracetamol, para-hydroxyacetanilide, APAP, NAPA, etc., is a widely used analgesic agent. Unfortunately the toxic nature of the drug when taken in overdose has been given wide publicity; and coupled with its ready availability this had led to the increasing use of this drug in suicide. The major organ affected by an overdose of N-acetyl-para-aminophenol is the liver; and even when an overdose is not fatal, it can cause severe liver damage.
Although this invention is not limited by any theoretical considerations, the following background explanation is offered. It is thought that hepatic damage induced by N-acetyl-para-aminophenol is related to the metabolism of the drug converting it into a highly chemically-reactive derivative, which binds covalently to liver cell proteins when the drug is given in overdose; whereas non-hepatotoxic doses of N-acetyl-para-aminophenol give rise to little or no convalent binding. Although the exact nature of the toxic metabolite is not known, it is thought to be a precursor of the cysteine and mercapturic acid conjugates of N-acetyl-para-aminophenol, as excretion of these conjugates increases significantly in the overdose situation.
The cysteine and mercapturic acid conjugates of N-acetyl-para-aminophenol are formed via the activation of the parent molecule to a chemically-unstable intermediate, which normally will immediately form a complex with reduced glutathione within the liver cell. In the overdose situation, however, activation of N-acetyl-para-aminophenol occurs faster than hepatic reduced glutathione can be synthesized; and as the level of glutathione falls, some of the reactive metabolite combines with hepatocyte proteins instead. The quantity of the chemically-unstable intermediate convalently bound to hepatocyte proteins correlates with the severity of the ensuing liver damage.
In the overdose situation, the logical antidote would therefore seem to be glutathione itself; but, if administered exogenously, glutathione fails to penetrate the cells, and is therefore ineffective unless massive doses are administered. Instead therefore it is conventional to treat overdoses with glutathione substitutes--sulfhydryl compounds--e.g., cysteamine or dimercaprol. It has been suggested that cysteamine may inhibit oxidation of N-acetyl-para-aminophenol to the toxic metabolite.
There is also a less obvious way of tackling the same problem. While an N-acetyl-para-aminophenol overdose results in glutathione depletion, it should be remembered that glutathione synthesis is still taking place-so by providing a glutathione precursor it should be possible to promote glutathione synthesis, thus to reduce the rate at which the glutathione levels fall, and in this way to keep the glutathione levels from falling to the low level at which the active N-acetyl-para-aminophenol metabolite starts to attack the hepatocyte proteins. Here again therefore it is conventional to treat overdoses of N-acetyl-para-aminophenol by providing a glutathione precursor, e.g., methionine or cysteine.
These conventional methods of treating overdoses of N-acetyl-para-aminophenol are however often ineffective, due to the time lapse between ingestion of the N-acetyl-para-aminophenol overdose and the arrival of the glutathione substitute or glutathione precursor in the liver cells.
The following references are summarized to show the state of the prior art:
A. E. M. McLean, THE LANCET, p. 729 (Apr. 20, 1974), first showed the combination of methionine with paracetamol as a way of greatly reducing the lethal and hepatotoxic effects of paracetamol overdosage. McLean concludes: "Methionine seems an easy way in which we can make paracetamol a safer drug" and also suggests the use of cystine as a substitute for methionine.
Maxwell et al., THE LANCET, pp. 610-611 (Sept. 27, 1975), reported that the above-noted McLean's study "demonstrated the decreased toxicity of the combination of acetaminophen and methionine in rats" and that "our study demonstrates it in dogs".
McLean and Day, "The Effect of Diet on the Toxicity of Paracetamol and the Safety of Paracetamol-Methionine Mixtures," Biochemical Pharmacology 24, 37-42 (1975)--The abstract reads in part: "Addition of methionine to oral paracetamol dose protects against death and liver injury, and it is suggested that this may be a useful technique for making paracetamol safe against the danger of overdose."
The National Research Development Corp. German Pat. Appln. 2,455,203, published May 22, 1975, (based on Appln. No. 455,203, filed Nov. 21, 1974, in turn, based on British Appln. No. 54,098, filed Nov. 21, 1973) is abstracted in the July 8, 1975 DERWENT.RTM. GERMAN PATENTS GAZETTE as follows:
"Medicaments contg. p-hydroxyacetanilide (I) as active ingredient also contain a cpd. (II) which is a precursor of the central amino acid grouping of glutathione and which can be converted into glutathione in vivo. (I) is widely used as an analgesic and antipyretic, but overdoses give rise to liver necrosis associated with the absence of glutathione in the liver; if an overdose of (I)+(II) is taken, this automatically leads to an increase in the glutathione synthesised in the organism, thus counteracting the toxic effects of the overdose. The glutathione precursor (II) can be an S-contg. amino acid, pref. DL- or L-cysteine, -cystine or -methionine (esp. the L-form), or a di- or tripeptide contg. such as amino acid. The medicament pref. contains 10-50% (esp. 10-30%) of (II), based on the wt. of (I). The medicaments are pref. administered orally (esp. as elixirs or tablets) in a unit dose of 0.24-1 g." PA1 N-Acetyl-para-aminophenyl N'-acetyl-methionate of the structural formula: ##STR3## (conforming to general formula I above, where n is 2 and X is a methyl group); PA1 N-Acetyl-para-aminophenyl N'-acetyl-cysteinate of the structural formula: ##STR4## (conforming to general formula I above, where n is 1 and X is a hydrogen atom); PA1 Di-(N-acetyl-para-aminophenyl) N',N"-diacetyl-cystinate of structural formula: ##STR5## (conforming to general formula I above, where n is 1 and X is the grouping of general formula I' where p is 1 and n' is 1); PA1 Di-(N-acetyl-para-aminophenyl) N',N"-diacetylcystathionate of structural formula: ##STR6## (conforming to general formula I above, where n is 1 and X is the grouping of general formula I' where p is 0 and n' is 2); PA1 N-Acetyl-para-aminophenyl N'-acetyl-S-methylcysteinate of the structural formula: ##STR7## (conforming to general formula I above, where n is 1 and X is a methyl group); and PA1 N-Acetyl-para-aminophenyl N'-acetyl-homocysteinate of the structural formula: ##STR8## (conforming to general formula I above, where n is 2 and X is a hydrogen atom). PA1 (a) the ingestible excipient of a tablet, coated tablet, or pill; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier or a powder; or the ingestible liquid medium of a syrup, solution, suspension or elixir; or PA1 (b) a base material of low melting point capable of releasing the active ingredient to perform its pharmacological function, which base material, when appropriately shaped, forms a suppository.
The Italchemi S.r.l.-Instituto Chimico Farmaceutico French BSM No. 4672M, published Jan. 23, 1967, shows as anti-inflammatory, anti-allergic, analgesic and antipyretic agents the paracetamol esters of gamma-aminobutyric acid, delta-aminovaleric acid and epsilon-aminocaproic acid and their N-acetyl derivatives.
Kovach, "Aminoacid esters of p-acetamidophenol as prodrugs", a Ph.D. thesis, University of Kansas, 1974 [C.A. 83, 193681t (1975)]; Diss. Abstr. Int. B 1975, 36(2), 734-5--The abstract of this thesis shows the preparation of paracetamol (APAP) esters of amino acids, specifically glycine, alpha-aspartic acid and beta-aspartic acid.
Piperno et al. (McNeil Labs. Inc., Fort Washington, Pa.), THE LANCET, pp. 738-739 (Oct. 2, 1976)--Letter to the editor with the title, "Reversal of Experimental Paracetamol Toxicosis with N-Acetylcysteine." The authors conclude that their data "suggest that N.A.C. sodium (N-acetylcysteine sodium) will be effective orally and parenterally in the clinic at doses approximately to 20-40% of the ingested amount of paracetamol."
Gerber et al. (Dept. of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tenn.), THE LANCET, pp. 657-658 (Mar. 19, 1977)--Letter to the editor with heading: "Effect of N-Acetylcysteine on Hepatic Convalent Biding or Paracetamol (Acetaminophen)." Gerber et al. reported that 1 g./kg. of N-acetylcysteine administered concurrently or 2 or 4 hours after 1.4 g./kg. of paracetamol "significantly improved 48 hour survival in mice".
Mead Johnson & Co. Sheffner U.S. Pat. No. 3,591,686, issued July 6, 1971 (based on Appln. Ser. No. 657,498, filed Aug. 1, 1967, in turn a C.I.P. of Appln. Ser. No. 482,931, filed Aug. 26, 1965) has "method-of-treating" and composition claims covering the use of N-acetylcysteine and related"--(N-acylamino)-.beta.-mercaptoalkanoic acids or salts thereof" as anti-inflammatory agents.